Emerging therapies in rosacea

Alison Layton, MB, ChB,a and Diane Thiboutot, MDb

Harrogate, United Kingdom, and Hershey, Pennsylvania

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Rosacea is a common skin disorder with multiple symptoms. The emergence of research that furthersunderstanding of pathophysiological mechanisms has created new targets for disease treatment. Specifically,there is a need for new treatments that address the various erythematic symptoms associated with rosacea.Systemic and topical therapies have both yielded positive results in treating rosacea with various medications.Subantimicrobial-dose doxycycline is one such promising treatment. Development of novel products in thenear future shouldhelp achievemore satisfactory outcomes for patients. ( J AmAcadDermatol 2013;69:S57-65.)

Key words: carvedilol; ivermectin; medical therapy; permethrin; rosacea; subantimicrobial-dosedoxycycline.

osacea represents a chronic inflammatory

Abbreviation used:

SDD: subantimicrobial dose doxycycline

R skin disorder with many clinical guises.These embrace transient and permanent er-

ythema, inflammatory papules and pustules, phym-atous changes, and ocular signs and symptoms.1 Thepathophysiology is multifactorial and as yet not fullydetermined. However, the understanding of mecha-nisms involved in the cause of rosacea are emergingand recent molecular studies suggest that an alteredinnate immune response is involved in both thevascular and inflammatory disease seen in patientswith rosacea. As appreciation of pathophysiologyunfolds, there is opportunity to target the specificpathogenic factors and related clinical manifestationswith novel agents. Numerous treatments, includingtopical metronidazole and azelaic acid and systemictetracyclines, have been shown to be efficacious forthe papules and pustules of rosacea.2,3 However, todate there have been few good treatment options forthe facial redness commonly seen in rosacea attrib-utable to inflammation and vascular change. Recentreports suggest novel therapies are on the horizon fortreating the erythema of rosacea. The followingoutlines treatment developments and discussesthe rationale for use and effect of low-dose cyclineantibiotics, b-blockers, and antiparasitic agents forrosacea-related erythema. Novel adrenergic receptoragonists are considered elsewhere in thissupplement.

the Departments of Dermatology at Harrogate District

ospital, United Kingdoma and Pennsylvania State University

ollege of Medicine, Hershey, Pennsylvania.b

ication of this article was supported by a grant from

alderma International. Editorial support provided by

alderma International.

osure: Dr Layton has served on advisory boards for Galderma,

SK, Meda, and Intendis and served on the board of directors

r PCOS UK, and received honoraria as compensation. Dr

iboutot has served as a consultant for Allergan, Galderma,

SYSTEMIC THERAPIESSubantimicrobial-dose cyclines

Appreciation of the inflammatory nature of rosa-cea and the growing concern about antibiotic-resistant bacteria emerging as a result of systemicantibiotics used in the management of a number ofinflammatory skin conditions has prompted interestin the use of subantimicrobial doses of tetracyclineantibiotics as a means of treating inflammation.There are currently 3 major tetracycline derivativesin clinical use: tetracycline, doxycycline, and mino-cycline. The antimicrobial activity of these agents isboth dose and concentration dependent; each alsohas anti-inflammatory actions that are unrelated toantibiotic activity and occur at lower doses thanthose required to achieve a bactericidal affect(Fig 1).4-11 There is recognition that rosacea haspathogenic factors that result in inflammatorychanges that are unrelated to bacteria but respondto antibiotic therapy.12 This has stimulated interest inexploiting the anti-inflammatory actions of the tetra-cyclines. In rosacea, subantimicrobial-dose doxycy-cline (SDD) is thought to act by multiple mechanisms(Table I).13,14 Cathelicidins are proinflammatory

Medicis, Photocure, Stiefel, and Valeant, and received honoraria

as compensation.

Accepted for publication April 21, 2013.

Reprint requests: Alison Layton, MB, ChB, Department of

Dermatology, Harrogate District Hospital, Lancaster Park

Road, Harrogate, United Kingdom HG2-7SX. E-mail: Alison.

layton@hhc-tr.northy.nhs.uk.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.04.041

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peptides linked to inflammation in rosacea. Mostrecently, doxycycline has been found to decrease theactivity for the kallikrein 5 enzyme that is responsiblefor generating activated cathelicidins from procathe-licidin.13 Doxycycline accomplishes this indirectly byinhibiting the matrix metalloproteinase enzymesresponsible for generating activated kallikrein. This

CAPSULE SUMMARY

d Rosacea is a common skin disorder withmultiple symptoms.

d New understanding in patho-physiological mechanisms has allowedfor development of novel treatments,such as subantimicrobial-dosedoxycycline, based on emergent diseasetargets.

d Development of novel products in thenear future should help achieve moresatisfactory outcomes for patients.

second-generation tetracy-cline is the first antibiotic tobe studied at doses that arenot bactericidal but haveanti-inflammatory action inrosacea and other condi-tions; once-daily SDD (40mg) has now been approvedby regulatory bodies fortreatment of rosacea.13,14

Microbial kinetics. SDDin dosage formulations of 20mg twice a day and once-daily 40-mg delayed releasehave both been sufficientlystudied to be granted non-antibiotic status by the US

Food and Drug Administration. In addition to phar-macokinetic studies, long-term microbiologic stud-ies have evaluated the impact of SDD on subgingival,intestinal, vaginal, and cutaneous flora.15,16 Asshown in Fig 2, SDD to date has no significantimpact on bacterial counts in skin. In addition,studies revealed no increase in flora resistant todoxycycline and no increase in minimum inhibitoryconcentrations of doxycycline after 9-month admin-istration of SDD.

Clinical efficacy on inflammatory skin le-sions in rosacea. Two phase III clinical trialsevaluated the efficacy and safety of SDD for thetreatment of moderate to severe rosacea.5 The stud-ies, which included a total of 537 subjects, over a16-week period, were randomized, double-blind,and placebo-controlled. Patients treated with SDDhad significantly greater reduction of total inflamma-tory lesions at week 16 compared with patients whoreceived placebo (P\ .001). This trend was evidentbeginning at week 3, with a greater decrease inlesion count in the SDD group compared with theplacebo group (P\.005), which continued throughto week 16.5 Post hoc analysis showed that theefficacy was consistent regardless of the number oflesions at baseline and body weight; indeed, SDDwas most effective in overweight patients with highnumbers of lesions at baseline. A separate studycompared SDD with doxycycline (100 mg) in pa-tients with moderate to severe papulopustular rosa-cea (N = 91).17 The results showed SDD achieved

lesion reductions that were comparable with thoseseen with traditional-dose doxycycline (Fig 3). Onepoint for consideration relates to the fact thesestudies did not consider different absorption coeffi-cients in individuals, which might also have influ-enced efficacy.17

Clinical efficacy of SDD on erythema

in rosacea. Clinician ery-thema assessment has beenconsidered as a secondaryefficacy end point in somestudies assessing SDD. Inone such study the meanreduction from baseline inmean clinician erythema as-sessment score was signifi-cantly greater at week 16 inthe actively treated subjectarm than the placebo group(P = .017) whereas facial er-ythema decreased amongsubjects in a second random-ized phase III trial evaluatinganti-inflammatory doxycy-

cline but the difference between the study groupsdid not reach significance.5

An open-label, community-based, 12-week as-sessment of the effectiveness and safety of mono-therapy with 40 mg of doxycycline (30-mgimmediate-release and 10-mg delayed-releasebeads) demonstrated that 75% of 1197 participantshas clinician erythema assessment scores reflectingno or mild erythema at the end of the study.18

Safety. Data from the phase III studies showedthat SDD is generally safe and well tolerated.5 Inthese controlled studies, there were no cases ofvaginal candidiasis or photosensitivity.5 Reports ofgastrointestinal upset were also low. In the studycomparing SDD with doxycycline (100 mg), the rateof gastrointestinal upset was 5 times higher withdoxycycline (100 mg).17

b-BlockersNonselective b-blockers decrease sympathetic

activity and also have been reported to suppressflushing, which results in transient redness, particu-larly in patients with comorbid anxiety.19 b-Blockersare thought to act on flushing by blocking theb-adrenergic receptors on smooth muscles of cuta-neous blood vessels, producing vasoconstriction.They may also reduce anxiety and tachycardia,which can exacerbate flushing reactions.20

Carvedilol, a newer nonselective b-blocker, hasmarked antioxidant and anti-inflammatory actions,which may contribute to an effect in rosacea.21

Fig 1. Anti-inflammatory actions of tetracyclines.4-11 NO, Nitric oxide; ROS, reactive oxygenspecies.

Table I. Probable anti-inflammatory actions of subantimicrobial-dose doxycycline in rosacea

1. Down-regulation of cytokinesSubsequent reduction of neutrophil infiltration deactivation of downstream inflammatory pathways

2. Inhibition of nitric oxideSubsequent reduction of vasodilation and cessation of capillary wall degradation that may reduce further leakage

3. Reduction of level of reactive oxygen speciesSlows destruction of connective tissue

4. Inhibition of matrix metalloproteinaseSlows destruction of connective tissue and capillary wallsIt may also reduce activation of cathelicidin-mediated inflammatory activities (according to recent data)Inhibits activation of kallikrein 5 leading to reduced production of proinflammatory cathelicidin

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There are only a few reports of b-blocker therapyin patients with rosacea. Craige and Cohen19 foundthat propranolol therapy (30-120 mg/d) was associ-ated with fewer and less severe flushing episodes in8 of 9 patients with rosacea. However, use of tradi-tional b-blockers in normotensive individuals islimited by concerns of hypotension andbradycardia.20

Hsu and Lee20,21 evaluated an alternative nonse-lective b-adrenergic receptor blocker, carvedilol, inrefractory facial flushing and persistent erythema ofrosacea with the implicit aims of achieving efficacywhile reducing the likelihood of adverse events. Inthe first report by these researchers, carvedilol suc-cessfully treated rosacea-associated redness in apatient with severe refractory symptoms.21 The pa-tient had both transient flushing and persistent ery-thema that had not responded to 4 weeks oftreatment with a multitude of agents, includingdoxycycline, fexofenadine hydrochloride, dexa-methasone, aspirin, topical corticosteroid, clonidine,

and pimecrolimus cream.20 In this case report, car-vedilol therapy (6.25 mg twice a day for 1 weekfollowed by 6.25 mg 3 times a day) achieved adramatic improvement in facial redness within 2weeks.20 The patient monitored her blood pressureand pulse at home, and there were no observationsof hypotension or bradycardia. The temperature ofthe skin on her cheek was reduced by 6.98C and herassessment of severity based on a 10-point visualanalog scale was reduced from a score of 10 to ascore of 1. The patient was maintained on a regimenof carvedilol, doxycycline (100 mg every other day),and pimecrolimus 1% for 23 months.20

In a second communication, Hsu and Lee21

reported good results with carvedilol therapyin 11 normotensive patients with rosacea unsuc-cessfully treated with numerous agents. The car-vedilol dose was titrated from 3.25 mg 3 times aday to 25 mg/d and assessments included facialerythema, cheek temperature, patient assessmentof severity, and adverse events. As shown in Fig 4,

Fig 2. Impact of subantimicrobial-dose doxycycline (SDD) on skin flora.

Fig 3. Reduction in papulopustular lesions with subantimicrobial-dose doxycycline (SDD) anddoxycycline (100 mg). Reprinted with permission from Del Rosso et al.17

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significant clinical improvements occurred within3 weeks of initiating therapy. In addition, themean cheek temperatures were reduced by 2.28Cand the patients’ assessments of severity im-proved (mean reduction of 6.3 on a 10-pointvisual analog scale).21 As the authors state, ‘‘low-dose carvedilol was effective in treating erythe-matotelangiectatic rosacea with rapid onset ofsymptom control.’’ Another encouraging findingwas that other medications were discontinued ortapered.21 Based on these preliminary results, it

seems that a larger scale controlled study wouldbe beneficial.21,20

Oral ivermectinSingle-dose oral ivermectin, a microfilaricide, has

been used in immunocompromised patients withrosacea-like demodicidosis with good effect.22-26

TOPICAL THERAPIESSeveral topical therapies are being investigated

for treatment of rosacea; all are primarily targeted

Fig 4. Clinical improvement in redness with carvedilol. Reprinted with permission from Hsuand Lee.20,21 TID, 3 times/wk.

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toward control of Demodex folliculorum and Dbrevis mites. Agents recently studied include 5%permethrin, 10% crotamiton, and 1% ivermectin, allantiparasitic agents that have been used for treat-ment of a variety of infections.

The potential causative role of Demodex mitesand associated commensals in the induction ofrosacea has been under debate for many years. Inhuman beings, 2 mite species (D brevis and Dfolliculorum) inhabit normal adult facial sebaceousfollicles; they are not present in the newborn butsebaceous follicles are thought to become colonizedduring adolescence. Many researchers considerthese mites to be a simple commensal on humanskin. However, there is increasing evidence thatthese mites may be opportunistic pathogens withthe potential to become parasitic if the host cutane-ous environment facilitates or promotes theirproliferation.

In many cases theDemodexwill live symbioticallywithin human skin living off host sebum and actingas a commensal. In this context the host’s innateimmune system remains tolerant to the presence ofthe Demodex mites. Hence, the presence ofDemodex is not necessarily considered a pathogenicfactor in the development of rosacea althoughDemodex proliferation has been considered as aprimary causative factor for papulopustular rosaceaby some authors27,28 and there are reports thatdemonstrate a higher density of D folliculorum in

patients with facial rosacea compared with controlsubjects.29 It has also been shown that proliferationof D folliculorum results in an inflammatory re-sponse conforming to a rosacea-like demodicidosisor Demodex dermatitis.25,28,30-33 One study demon-strated a linear correlation between the presence ofD folliculorum and the levels of fibroblast-relatedmatrix metalloproteinases-9 in patients with rosa-cea,34 supporting the fact that D folliculorum prolif-eration in patients with papulopustular rosacea mayrepresent an inflammatory cofactor. Use of topicalagents with immunomodulatory effects includingcalcineurin antagonists have been reported to resultin a rosacea-like dermatitis alongside an increase ofD folliculorum mites.35 Increased numbers of Dfolliculorummites in a patient with rosacea receivingan epidermal growth inhibitor (epidermal growthfactor inhibitor) for cancer has also been reported.The authors hypothesized that the epidermal growthfactor inhibitor was implicated in reducing the cuta-neous defense mechanisms enabling the prolifera-tion of Demodex.36 This concept around theparticular physical barrier of the skin is of interestand it has been shown that patients with papulopus-tular rosacea have an increased facial pH and re-duced skin surface hydration.37 These patients alsohave abnormal fatty acid composition of their skinsurface lipid layer, with increased levels of myristicacid and linoleic acid and reduced levels of saturatedfatty acids.38

Fig 5. Rosacea-like dermatitis before (A and B) and 6 weeks after (C and D) treatment withivermectin. Reprinted with permission from Forstinger et al.25

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Several other reports have confirmed that immu-nosuppression associated with HIV and AIDS,23,39

chemotherapy for childhood leukemia,40 chronicdialysis,41 and use of phototherapy42 leads to anincrease in the number of Demodex mites.

A recent meta-analysis has shown a significantassociation between Demodex species infestationand development of rosacea.43

These reports also suggest that an increase in thecritical mass of the mite can trigger inflammatorymechanisms that result in visible cutaneous inflam-mation. It is not clear whether the change in cutane-ous microenvironment contributes to miteproliferation and/or the aberrant innate immuneresponse allows for mite proliferation to the pointwhere a humoral response is initiated and subse-quent cutaneous inflammation ensues. However,previous studies and case reports would favor thelatter as a contributing factor and one hypothesisposes that Demodex mites, like other cutaneousmicrobes, can take on different roles according tothe host status.44

Renewed interest in Demodex has arisen fromrecent work that has identified a D folliculorumeas-sociated bacterium (Bacillus oleronius) isolated from

patients with papulopustular rosacea. It has beensuggested that B oleronius produces antigenic pro-teins that may play a role in papulopustular andocular rosacea.45

A further recent study has demonstrated thatpatients with erythematotelangiectatic rosaceashow serum reactivity to 2 proteins from B oleroniussuggesting that this bacterium may play a role in theinduction of erythematotelangiectatic rosacea. Theproteins implicated were found to be similar to heatshock protein and an enzyme involved in regulatingstress response of the bacterium.46

PermethrinThere have been several case reports about use of

topical permethrin in rosacea, usually in combina-tion with or after oral ivermectin therapy.22,23,25

Aquilina et al23 found that oral ivermectin plustopical permethrin effectively resolved a rosacea-like facial Demodex infection in a patient withimmune compromise. The patient had no responseto either topical ketoconazole or metronidazole andhad recent onset of rosacea-like papules and pus-tules associated with erythema, edema, and scales.Skin scraping and histologic examination of skin

Fig 6. Facial skin improvement in patients treated with topical crotamiton 10%. Reprinted withpermission from Bikowski and Del Rosso.33

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biopsy specimen showed a high concentration ofDemodex. Because of the high numbers of mites andexisting medications for comorbid conditions, anacaricidal regimen was prescribed. Within 2 weeks,there was a marked reduction in symptoms; topicalpermethrin cream was used to maintain results andno recurrence was reported after 1-year follow-up.

Allen et al22 reported successful treatment withoral ivermectin and topical permethrin in an immu-nocompetent patient with papulopustular rosaceathat was refractory to other therapies. However,these researchers thought that Demodex infestationhad a prominent role in the case, and noted theywould make a diagnosis of rosacea-like demodici-dosis. Notably, the patient had previously beentreated unsuccessfully with topical permethrinalone, and skin scrapings and biopsy specimenshowed significant follicular colonization withDemodex despite permethrin monotherapy.22

Similarly, Forstinger et al25 reported successful treat-ment of Demodex-associated rosacea symptoms in aman who had been refractory to conventional treat-ment (Fig 5). As in the other cases, this patient hadnumerous Demodex mites on skin scraping andhistology, and a regimen of oral ivermectin followedby topical permethrin was prescribed.30 Markedsymptomatic relief occurred within 2 weeks of theinitial dose of oral ivermectin, and once-weeklytopical permethrin was efficacious in maintainingresults.25

CrotamitonBikowski and Del Rosso33 performed a retrospec-

tive analysis of topical crotamiton treatment inpatients with rosacea-like Demodex dermatitis. In63 patients who had facial redness and rash, crotam-iton 10% cream/lotion monotherapy twice dailyresulted in a 50% or greater reduction in symptomsin 90.6% (56 of 62) (Fig 6). Noting that patients withrecurrent, unchanged erythema, dryness/scaling,and roughness with or without papules and pustuleshad marked improvement even when diagnostictesting did not confirm presence of Demodex mites,the authors noted that ‘‘empirical treatment forDemodex dermatitis using crotamiton is beneficialfor patients with these unresolved signs andsymptoms.’’33

Although as noted above topical crotamiton 10%or permethrin 5% have been used to reduce thenumbers of D folliculorum, they are frequentlyirritating and are therefore not tolerated well in allpatients.

IvermectinIvermectin is a strong acaricide with efficacy

against Demodex in case reports.24,26 Topical formu-lations of ivermectin are being investigated in severalconditions, including rosacea. In a recent controlledstudy of scabies, topical ivermectin 1% had efficacythat was more rapid than oral ivermectin and com-parable with topical permethrin, and the authors

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concluded that ‘‘topical ivermectin can be used as analternative to permethrin.’’47

The significant impact on Demodex and possiblyanti-inflammatory properties of topical ivermectinhas prompted investigation into the development ofa topical product. Controlled trials examining theimpact of topical ivermectin in rosacea are underwayand results should be available in the near future.48

CONCLUSIONSRosacea continues to pose a significant clinical

challenge; the clinical erythema associated withrosacea relates not only to the color associated withpapules and pustules but also to the transient andpersistent redness that frequently persists after ef-fective treatment of the inflammatory lesions. Thereis currently an unmet need for new treatments,particularly those targeted toward resolving persis-tent erythema.

To date, there have been few effective treatmentsfor erythema; patients are advised to avoid triggersinvolved in the innate immune response. However,although important, this does not achieve a satisfac-tory response in many cases. New treatments are onthe horizon, and we look forward to seeing newproducts become available in the near future.

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